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Original Research

Pharmacokinetics of a fixed-dose glimepiride/sustained-release metformin combination

Kyu-pyo Kim, Kyoung Soo Lim, Bo-Hyung Kim, Hyun-Suk Shin, Joo-Youn Cho, Sang-Goo Shin, In-Jin Jang and Kyung-Sang Yu

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Volume 50 p. 142 - 149

Abstract

International Journal of Clinical Pharmacology and Therapeutics, Vol. 50 – No. 2/2012 (142-149)

Pharmacokinetics of a fixed-dose glimepiride/sustained-release metformin combination

Kyu-pyo Kim¹*, Kyoung Soo Lim*, Bo-Hyung Kim, Hyun-Suk Shin, Joo-Youn Cho, Sang-Goo Shin, In-Jin Jang and Kyung-Sang Yu

Department of Pharmacology and Clinical Pharmacology, Seoul National University College of Medicine and Hospital, Seoul, Korea

*Both authors contributed equally to this work.
¹Current affiliation: Department of Internal Medicine, Ulsan University College of Medicine and Asan Medical Center, Seoul, Korea
Objective: Pharmacokinetic (PK) profiles of glimepiride and metformin have been established for the combination drug as well as each agent individually. However, the PK profiles of a combination drug containing glimepiride and sustainedrelease (SR) metformin have not been reported. To compare the pharmacokinetic profiles of glimepiride/SR metformin (2 mg/500 mg) with the PK of immediate-release (IR) formulations, an open-label, randomized, 3-period, 3-sequence, 3-treatment, crossover study was conducted in 12 healthy subjects. Methods: After a single administration of glimepiride/SR metformin 2 mg/500 mg (Treatment) or glimepiride/metformin IR 2 mg/500 mg (Reference 1), or administration of 2 doses of glimepiride/metformin IR 1 mg/250 mg 12 h apart (Reference 2), serial blood samples were collected and drug concentrations determined by liquid chromatography/ tandem mass spectrometry. PK parameters (C_max and AUC₂₄) for glimepiride and metformin were log-transformed and compared using a mixed-effects model analysis of variance (ANOVA). The mean differences and 95% confidence intervals (CIs) were back-transformed to obtain geometric mean ratios along with the CIs for the ratios. Results: Treatment demonstrated similar systemic exposures for glimepiride; the geometric mean ratio (95% CIs) for glimepiride AUC₂₄ was 1.05 (0.97 – 1.13) for Treatment relative to Reference 1 and 1.08 (1.00 – 1.17) for Treatment relative to Reference 2. The SR formulation showed a delay in the time to reach maximum concentration for metformin from 1.0 – 4.0 h to 4.0 – 8.0 h and a decreased AUC₂₄ value; the geometric mean ratio for metformin AUC₂₄ was 0.87 (0.74 – 1.03) for Treatment relative to Reference 1 and 0.75 (0.63 – 0.88) for Treatment relative to Reference 2. Conclusions: This study demonstrates for the first time that fixed-dose glimepiride and SR metformin 2 mg/500 mg shows a PK profile similar to that of glimepiride, but with a delayed time to maximum concentration and slightly decreased bioavailability for metformin compared with the IR fixed-dose combination, in healthy volunteers. PK profiles from this exploratory study will be helpful in designing and conducting further studies in diabetic patients.Correspondence to:
Kyung-Sang Yu, MD, PhD
Department of Pharmacology and Clinical Pharmacology
National University College of Medicine and Hospital
101 Daehangno, Jongno-gu, Seoul 110-744, Korea
Email: [email protected]

Original Research

Evaluation of the pharmacokinetic interaction between the dipeptidyl peptidase IV inhibitor LC15-0444 and pioglitazone in healthy volunteers

Sung Eun Kim, SoJeong Yi, Kwang-Hee Shin, Tae-Eun Kim, Min-Jeong Kim, Youn Hoa Kim, Seo Hyun Yoon, Joo-Youn Cho, Sang-Goo Shin, In-Jin Jang and Kyung-Sang Yu

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Volume 50 p. 17 - 23

Abstract

Evaluation of the pharmacokinetic interaction between the dipeptidyl peptidase IV inhibitor LC15-0444 and pioglitazone in healthy volunteers

Sung Eun Kim¹, SoJeong Yi¹, Kwang-Hee Shin¹, Tae-Eun Kim¹, Min-Jeong Kim², Youn Hoa Kim³, Seo Hyun Yoon¹, Joo-Youn Cho¹, Sang-Goo Shin¹, In-Jin Jang¹ and Kyung-Sang Yu¹

¹Department of Pharmacology and Clinical Pharmacology, Seoul National University College of Medicine and Hospital, ²Department of Clinical Development and ³Department of DMPK, LG Life Sciences, Ltd, Seoul, Republic of Korea
Objective: LC15-0444, a newly developed selective dipeptidyl peptidase IV inhibitor, has the potential to be administered with other antihyperglycemic agents. The aim of this study was to investigate the interaction between LC15-0444 and pioglitazone by comparing the pharmacokinetics of both compounds and their metabolites. Methods: A randomized, open-label, multiple dosing, three-sequence, three-period, three-treatment crossover study was performed in healthy volunteers. The three treatment groups were comprised of LC15-0444 200 mg, pioglitazone 30 mg, or coadministration of both drugs once daily for 12 days. Blood samples were collected up to 48 hours after the last dosing. Safety and tolerability were assessed throughout the study. Results: The geometric mean ratios (GMRs; (LC15-0444+Pioglitazone coadministered)/(LC15-0444 or Pioglitazone alone)) (90% confidence intervals (CIs)) for C_max,ss and AUC_t,ss of LC15-0444 were 1.06 (0.96 – 1.16) and 0.98 (0.93 – 1.03), respectively. In the case of pioglitazone, the GMRs (90% CIs) for C_max,ss and AUC_t,ss were 0.84 (0.73 – 0.96) and 0.85 (0.76 – 0.96), respectively. All reported adverse events were mild in intensity. Conclusions: The pharmacokinetics of LC15-0444 and its metabolites were not altered by pioglitazone. The systemic exposure of pioglitazone was decreased by 15% after coadministration of LC15-0444 with pioglitazone, but this was not judged to be clinically relevant, considering the total active moiety of pioglitazone.Correspondence to:
K.-S. Yu, MD, PhD
Department of Pharmacology and Clinical Pharmacology
Seoul National University
College of Medicine and Hospital
101 Daehak-ro, Jongno-gu,
Seoul 110-744, Korea
Email: [email protected]

Original Research

Multiple-dose pharmacokinetics of fesoterodine sustained-release in healthy Korean volunteers

Dongseong Shin, Kwang-Hee Shin, SeungHwan Lee, Kyoung Soo Lim, Joo-Youn Cho, In-Jin Jang, Sang-Goo Shin and Kyung-Sang Yu

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Volume 50 p. 722 - 728

Abstract

International Journal of Clinical Pharmacology and Therapeutics, Vol. 50 – No. 10/2012 (722-728)

Multiple-dose pharmacokinetics of fesoterodine sustained-release in healthy Korean volunteers

Dongseong Shin, Kwang-Hee Shin, SeungHwan Lee, Kyoung Soo Lim, Joo-Youn Cho, In-Jin Jang, Sang-Goo Shin and Kyung-Sang Yu

Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine and Hospital, Seoul, Korea
Objective: Fesoterodine is a pro-drug of the active metabolite 5-hydroxymethyl tolterodine (5-HMT), a muscarinic receptor antagonist. This study aimed to evaluate the safety profile and pharmacokinetic characteristics of multiple oral doses of sustained-release fesoterodine (fesoterodine SR) in healthy Korean males. Methods: A randomized, double-blind, placebo-controlled, multiple-dose study with two oral doses (4 mg and 8 mg) was conducted in healthy Korean male participants. The study drug was administered once daily for 5 days. The plasma concentration of 5-HMT was measured up to 72 hours after the last drug administration. The CYP2D6 genotype was analyzed using polymerase chain reaction (PCR) methods to assess the effect of genetic polymorphisms on the pharmacokinetic parameters. Results: 20 participants completed the study. The mean (SD) areas under the plasma concentration-time curves during the dosing interval (AUC_τ) of the 4 mg and 8 mg dose groups were 26.1 (8.0) and 64.2 (30.5) μg∙h/ml and the mean peak concentrations (C_max) were 2.6 (0.7) and 6.0 (2.0) μg/ml, respectively, at steady-state. The mean AUC_τ and C_max of 5-HMT increased in approximately the same proportion as the dose increased. Fesoterodine SR was well tolerated without any serious adverse events or abnormal clinical laboratory findings. Conclusion: Systemic 5-HMT exposure showed dose-proportional characteristics in the 4 mg to 8 mg dose range in healthy Korean males. Thus, 4 mg or 8 mg doses of fesoterodine SR taken once-daily were tolerable in healthy Korean males.Correspondence to:
Kyung-Sang Yu, MD, PhD
Department of Clinical Pharmacology and Therapeutics Seoul
National University College of Medicine and Hospital Seoul
101 Daehangno, Jongno-gu
Seoul 110-744, Korea
Email: [email protected]

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